Novel targeted deregulation of c-Myc cooperates with Bcl-XL to cause plasma cell neoplasms in mice
Wan Cheung Cheung, … , Roberto D. Polakiewicz, Siegfried Janz
Wan Cheung Cheung, … , Roberto D. Polakiewicz, Siegfried Janz
Published June 15, 2004
Citation Information: J Clin Invest. 2004;113(12):1763-1773. https://doi.org/10.1172/JCI20369.
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Article Oncology

Novel targeted deregulation of c-Myc cooperates with Bcl-XL to cause plasma cell neoplasms in mice

Abstract

Deregulated expression of both Myc and Bcl-XL are consistent features of human plasma cell neoplasms (PCNs). To investigate whether targeted expression of Myc and Bcl-XL in mouse plasma cells might lead to an improved model of human PCN, we generated Myc transgenics by inserting a single-copy histidine-tagged mouse Myc gene, MycHis, into the mouse Ig heavy-chain Cα locus. We also generated Bcl-XL transgenic mice that contain a multicopy Flag-tagged mouse Bcl-xFlag transgene driven by the mouse Ig κ light-chain 3′ enhancer. Single-transgenic Bcl-XL mice remained tumor free by 380 days of age, whereas single-transgenic Myc mice developed B cell tumors infrequently (4 of 43, 9.3%). In contrast, double-transgenic Myc/Bcl-XL mice developed plasma cell tumors with short onset (135 days on average) and full penetrance (100% tumor incidence). These tumors produced monoclonal Ig, infiltrated the bone marrow, and contained elevated amounts of MycHis and Bcl-XLFlag proteins compared with the plasma cells that accumulated in large numbers in young tumor-free Myc/Bcl-XL mice. Our findings demonstrate that the enforced expression of Myc and Bcl-XL by Ig enhancers with peak activity in plasma cells generates a mouse model of human PCN that recapitulates some features of human multiple myeloma.

Authors

Wan Cheung Cheung, Joong Su Kim, Michael Linden, Liangping Peng, Brian Van Ness, Roberto D. Polakiewicz, Siegfried Janz

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Figure 1

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Experimental overview of the generation of double-transgenic Myc/Bcl-XL ...
Experimental overview of the generation of double-transgenic Myc/Bcl-XL mice. (A) Generation of Myc transgenic mice. Shown are the normal mouse Igh locus (top) and the targeted Igh locus with the inserted MycHis gene (bottom). The transcriptional orientation of Igh and MycHis is indicated by a black and a red arrow, respectively. (B) Generation of Bcl-XL transgenic mice. Depicted is a scheme of the Bcl-x transgene, which consists of the mouse 3′ κ enhancer; the promoter of the mouse variable κ gene, Vκ21; the mouse Bcl-x cDNA fused to the Flag epitope_encoding sequence; and the 3′ untranslated region of the human growth hormone (3′ hGH), a facilitator of Bcl-x expression. (C) Myc/Bcl-XL bitransgenics were on a mixed genetic background containing alleles from strains C57BL/6, 129SvJ, and FVB/N.